Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension.

Abstract

The genetic basis of familial primary pulmonary hypertension (FPPH) is unknown, but the clinical and pathologic features are the same as in sporadically occurring primary pulmonary hypertension (PPH). Because few families with this disease have been reported, the mode of inheritance and genetic features have not been clearly established. We previously reported a tendency for decreasing age of onset in subsequent generations of affected families. The purpose of this study was to examine the pattern of inheritance in a large number of families in an attempt to find clues to pathogenesis. From 24 families we studied 429 members, 124 of whom were known to carry the gene for disease. We constructed cumulative mortality curves for each gender of the 99 affected individuals. We analyzed gender ratios of progeny of affected members and carriers and compared age at death of affected members by generation. More females (160) than males (122) were born to persons carrying the gene, p < 0.01, suggesting selective wastage of male fetuses or an abnormal primary sex ratio. Genetic anticipation was confirmed; the age at death was 45.6 +/- 14.5 versus 36.3 +/- 12.6 versus 24.2 +/- 11 standard deviation (SD) years in successive generations, p < 0.05. Five cases of male-to-male transmission were observed, excluding X-linkage. Age at death was the same for males and females. More females had the gene (84 females, 40 males) and more females with the gene developed disease (72 of 84 females [86%] versus 27 of 40 males [68%]). The disease has highly variable penetrance among families.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary Hypertension: Diagnosis and Management

“…The penetrance of the allelic variant is low (mean, 20%; variable among families). 19 Thus, only 1 in 5 people with a BMPR2 allelic variant exhibit features of PAH, and 1 in 10 offspring of people carrying the variant gene will develop PAH.…”

Update on Pediatric Pulmonary Arterial Hypertension

“…This phenomenon is controversial but is typically observed in diseases with trinucleotide repeat expansion. 5 As for associated PAH (APAH), collagen vascular diseaserelated PAH is rare in children, but a report from China found PAH in 5 of 8 (62.5%) pediatric patients with connective tissue disease (CTD), 2 of 4 (50%) with antiphospholipid antibody syndrome, 4 of 14 (28.6%) with systemic vasculitis, 3 of 28 (10.9%) with dermatomyositis, and 17 of 223 (7.6%) with systemic lupus erythematosus. 6 Antinuclear antibody positivity has not been found in children with PAH but was observed in 4 of 16 (25%) mothers of children with IPAH.…”

Pulmonary hypertension—“state of the art” management in 2012

“…the onset of disease occurs at an Indian Heart Journal 6401 (2012) [60][61][62][63][64][65][66][67][68][69][70][71][72][73] earlier age in successive generations. 8,9 Group 1 of Dana Point classification also includes drugs and toxins associated with development of PAH; the most notorious of these include the appetite suppressants fenfluramine and dexfenfluramine. More recently, methamphetamine is being indicated as the cause of drug-related PAH.…”